Method of making phosphate-binding polymers for oral administration

ABSTRACT

Phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract. The polymers are orally administered, and are useful for the treatment of hyperphosphatemia.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Ser. No. 09/542,329,filed Apr. 4, 2000, now allowed, which is a continuation of U.S. Ser.No. 08/929,784, filed Sep. 15, 1997, now U.S. Pat. No. 6,083,495, whichis a divisional of U.S. Ser. No. 08/471,747, filed Jun. 6, 1995, nowU.S. Pat. No. 5,667,775, which is a continuation-in-part of U.S. Ser.No. 08/238,458, filed May 5, 1994, now U.S. Pat. No. 5,496,545, which isa continuation-in-part of U.S. Ser. No. 08/105,591, filed Aug. 11, 1993,now abandoned, the entire teachings of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] Hyperphosphatemia frequently accompanies diseases associated withinadequate renal function, hypoparathyroidism, and certain other medicalconditions. Hyperphosphatemia is typically defined as possessing a serumphosphate levels of over about 6 mg/dL. The condition, especially ifpresent over extended periods of time, leads to severe abnormalities incalcium and phosphorus metabolism and can be manifested by aberrantcalcification in joints, lungs, and eyes.

[0003] Therapeutic efforts to reduce serum phosphate include dialysis,reduction in dietary phosphate, and oral administration of insolublephosphate binders to reduce gastrointestinal absorption. Dialysis andreduced dietary phosphate are generally unsuccessful in adequatelyreversing hyperphosphatemia. Further difficulties in these therapeuticregimens include the invasive nature of dialysis and the difficulties inmodifying dietary habits in the latter therapy.

[0004] The oral administration of certain phosphate binders has alsobeen suggested. Phosphate binders include calcium or aluminum salts.Calcium salts have been widely used to bind intestinal phosphate andprevent absorption. The ingested calcium combines with phosphate to forminsoluble calcium phosphate salts such as Ca₃(PO₄)₂, CaHPO₄, orCa(H₂PO₄)₂. Different types of calcium salts, including calciumcarbonate, acetate (such as PhosLo® calcium acetate tablets), citrate,alginate, and ketoacid salts have been utilized for phosphate binding.This class of therapeutics generally results in hypercalcemia due fromabsorption of high amounts of ingested calcium. Hypercalcemia has beenindicated in many serious side effects, such as cardiac arrhythmias,renal failure, and skin and visceral calcification. Frequent monitoringof serum calcium levels is required during therapy with calcium-basedphosphate binders.

[0005] Aluminum-based phosphate binders, such as Amphojel® aluminumhydroxide gel, have also been used for treating hyperphosphatemia. Thesecompounds complex with intestinal phosphate to form highly insolublealuminum phosphate; the bound phosphate is unavailable for absorption bythe patient. Prolonged use of aluminum gels leads to accumulations ofaluminum, and often to aluminum toxicity, accompanied by such symptomsas encephalopathy, osteomalacia, and myopathy.

[0006] Selected ion exchange resins have also been suggested for use inbinding phosphate. Those tested include Dowex® anion-exchange resins inthe chloride form, such as XF 43311, XY 40013, XF 43254, XY 40011, andXY 40012. These resins have several drawbacks for treatment ofhyperphosphatemia, including poor binding efficiency, necessitating useof high dosages for significant reduction of absorbed phosphate.

[0007] Thus a need exists for improved phosphate binders which can beadministered orally in acceptable dosage levels without resulting inmany of the serious side effects discussed above.

SUMMARY OF THE INVENTION

[0008] The invention relates to the discovery that a class of anionexchange polymers have improved phosphate binding properties. Ingeneral, the invention features a method of removing phosphate from apatient by ion exchange, which involves oral administration of atherapeutically effective amount of a composition containing at leastone phosphate-binding polymer. The polymers of the invention may becrosslinked with a crosslinking agent.

[0009] The invention provides an effective treatment for decreasing theserum level of phosphate by binding phosphate in the gastrointestinaltract, without comcomittantly increasing the absorption of anyclinically undesirable materials, particularly calcium or aluminum.

[0010] Other features and advantages will be apparent from the followingdescription of the preferred embodiments and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1 is an illustration of the bound phosphate relevant tosolution phosphate concentration after a phosphate solution is treatedwith poly(dimethylaminopropyl-acrylamide).

[0012]FIG. 2 is a graphic illustration of the phosphate concentration infecal samples taken from rats fed with a dietary supplement of acrosslinked polyallylamine and micro-crystalline cellulose (placebo).

[0013]FIG. 3 is a graphic illustration of the urinary phosphateconcentration in rats similarly given a dietary supplement of acrosslinked polyallylamine and micro-crystalline cellulose (placebo).

DETAILED DESCRIPTION OF THE INVENTION

[0014] A description of preferred embodiments of the invention follows.

[0015] The polymers of the invention generally include hydrophilic anionexchange resins, particularly aliphatic amine polymers. The “amine”group can be present in the form of a primary, secondary or tertiaryamine, quaternary ammonium salt, amidine, guanadine, hydrazine, orcombinations thereof. The amine can be within the linear structure ofthe polymer (such as in polyethylenimine or a condensation polymer of apolyaminoalkane, e.g. diethylenetriamine, and a crosslinking agent, suchas epichlorohydrin) or as a functional group pendant from the polymerbackbone (such as in polyallylamine, polyvinylamine orpoly(aminoethyl)acrylate).

[0016] In one aspect, the polymer is characterized by a repeating unithaving the formula

[0017] or a copolymer thereof, wherein n is an integer and each R,independently, is H or a substituted or unsubstituted alkyl, such as alower alkyl (e.g., having between 1 and 5 carbon atoms, inclusive),alkylamino (e.g., having between 1 and 5 carbons atoms, inclusive, suchas ethylamino) or aryl (e.g., phenyl) group.

[0018] In a second aspect, the polymer is characterized by a repeatingunit having the formula

[0019] or a copolymer thereof, wherein n is an integer, each R,independently, is H or a substituted or unsubstituted alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl (e.g., phenyl) group, and each X⁻ is an exchangeable negativelycharged counterion.

[0020] One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula

[0021] wherein n is an integer, each R, independently, is H or asubstituted or unsubstituted alkyl (e.g., having between 1 and 5 carbonatoms, inclusive), alkylamino (e.g., having between 1 and 5 carbonsatoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl), andeach X⁻ is an exchangeable negatively charged counterion; and furthercharacterized by a second repeating unit having the formula

[0022] wherein each n, independently, is an integer and each R,independently, is H or a substituted or unsubstituted alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl group (e.g., phenyl).

[0023] In a fourth aspect, the polymer is characterized by a repeatingunit having the formula

[0024] or a copolymer thereof, wherein n is an integer, and R is H or asubstituted or unsubstituted alkyl (e.g., having between 1 and 5 carbonatoms, inclusive), alkylamino (e.g., having between 1 and 5 carbonsatoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl).

[0025] One example of a copolymer according to the second aspect of theinvention is characterized by a first repeating unit having the formula

[0026] wherein n is an integer, and R is H or a substituted orunsubstituted alkyl (e.g., having between 1 and 5 carbon atoms,inclusive), alkylamino (e.g., having between 1 and 5 carbons atoms,inclusive, such as ethylamino) or aryl group (e.g., phenyl); and furthercharacterized by a second repeating unit having the formula

[0027] wherein each n, independently, is an integer and R is H or asubstituted or unsubstituted alkyl (e.g., having between 1 and 5 carbonatoms, inclusive), alkylamino (e.g., having between 1 and 5 carbonatoms, inclusive, such as ethylamino) or aryl group (e.g., phenyl).

[0028] In a fifth aspect, the polymer is characterized by a repeatinggroup having the formula

[0029] or a copolymer thereof, wherein n is an integer, and each R₁ andR₂, independently, is H or a substituted or unsubstituted alkyl (e.g.,having between 1 and 5 carbon atoms, inclusive), and alkylamino (e.g.,having between 1 and 5 carbons atoms, inclusive, such as ethylamino) oraryl group (e.g., phenyl), and each X⁻ is an exchangeable negativelycharged counterion.

[0030] In one preferred polymer according to the fifth aspect of theinvention, at least one of the R groups is a hydrogen atom.

[0031] In a sixth aspect, the polymer is characterized by a repeat unithaving the formula

[0032] or a copolymer thereof, where n is an integer, each R₁ and R₂,independently, is H, a substituted or unsubstituted alkyl groupcontaining 1 to 20 carbon atoms, an alkylamino group (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino), or anaryl group containing 6 to 12 atoms (e.g., phenyl).

[0033] In a seventh aspect, the polymer is characterized by a repeatunit having the formula

[0034] or a copolymer thereof, wherein n is an integer, each R₁, R₂ andR₃, independently, is H, a substituted or unsubstituted alkyl groupcontaining 1 to 20 carbon atoms, an alkylamino group (e.g., havingbetween 1 and 5 carbons atoms, inclusive, such as ethylamino), or anaryl group containing 6 to 12 atoms (e.g., phenyl), and each X⁻ is anexchangeable negatively charged counterion.

[0035] In each case, the R groups can carry one or more substituents.Suitable substituents include therapeutic anionic groups, e.g.,quaternary ammonium groups, or amine groups, e.g., primary and secondaryalkyl or aryl amines. Examples of other suitable substituents includehydroxy, alkoxy, carboxamide, sulfonamide, halogen, alkyl, aryl,hydrazine, guanadine, urea, and carboxylic acid esters, for example.

[0036] The polymers are preferably crosslinked, in some cases by addinga crosslinking agent to the reaction mixture during or afterpolymerization. Examples of suitable crosslinking agents are diacrylatesand dimethacrylates (e.g., ethylene glycol diacrylate, propylene glycoldiacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate,propylene glycol dimethacrylate, butylene glycol dimethacrylate,polyethyleneglycol dimethacrylate, polyethyleneglycol diacrylate),methylene bisacrylamide, methylene bismethacrylamide, ethylenebisacrylamide, epichlorohydrin, epibromohydrin, toluene diisocyanate,ethylenebismethacrylamide, ethylidene bisacrylamide, divinyl benzene,bisphenol A dimethacrylate, bisphenol A diacrylate, 1,4butanedioldiglycidyl ether, 1,2 ethanedioldiglycidyl ether,1,3-dichloropropane, 1,2-dichloroethane, 1,3-dibromopropane,1,2-dibromoethane, succinyl dichloride, dimethylsuccinate, acryloylchloride, or pyromellitic dianhydride.

[0037] The amount of crosslinking agent is typically between about 0.5and about 75 weight %, and preferably between about 1 and about 25% byweight, based upon the combined weight of crosslinking and monomer. Inanother embodiment, the crosslinking agent is present between about 2and about 20% by weight of polymer.

[0038] In some cases the polymers are crosslinked after polymerization.One method of obtaining such crosslinking involves reaction of thepolymer with difunctional crosslinkers, such as epichlorohydrin,succinyl dichloride, the diglycidyl ether of bisphenol A, pyromelliticdianhydride, toluence diisocyanate, and ethylenediamine. A typicalexample is the reaction of poly(ethyleneimine) with epichlorohydrin. Inthis example the epichlorohydrin (1 to 100 parts) is added to a solutioncontaining polyethyleneimine (100 parts) and heated to promote reaction.Other methods of inducing crosslinking on already polymerized materialsinclude, but are not limited to, exposure to ionizing radiation,ultraviolet radiation, electron beams, radicals, and pyrolysis.

[0039] Examples of preferred crosslinking agents includeepichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane,1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride,dimethylsuccinate, toluene diisocyanate, acryloyl chloride, andpyromellitic dianhydride.

[0040] The negatively charged counterions, X⁻, can be organic ions,inorganic ions, or a combination thereof. The inorganic ions suitablefor use in this invention include halide (especially chloride),carbonate, bicarbonate, sulfate, bisulfate, hydroxide, nitrate,persulfate and sulfite. Suitable organic ions include acetate,ascorbate, benzoate, citrate, dihydrogen citrate, hydrogen citrate,oxalate, succinate, tartrate, taurocholate, glycocholate, and cholate.

[0041] In a preferred embodiment, the counterion does not have adetrimental side effect to the patient but rather is selected to have atherapeutic or nutritional benefit to the patient.

EXAMPLES

[0042] Candidate polymers were tested by stirring them in a phosphatecontaining solution at pH 7 for 3 hours. The solution was designed tomimic the conditions present in the small intestine. Solution Contents10-20 mM Phosphate 80 mM Sodium Chloiride 30 mM Sodium Carbonate

[0043] The pH was adjusted to pH 7, once at the start of the test andagain at the end of the test, using either aqueous NaOH or HCl. After 3hours the polymer was filtered off and the residual phosphateconcentration in the test solution was determinedspectrophotometrically. The difference between the initial phosphateconcentration and the final concentration was used to determine theamount of phosphate bound to the polymer. This result is expressed inmilliequivalents per gram of starting polymer (meq/g).

[0044] Table 1 below shows the results obtained for several polymers.Higher numbers indicate a more effective polymer. TABLE 1 PhosphateBound Polymer (meq/g)* Poly(allylamine/epichlorohydrin) 3.1Poly(allylamine/butanediol diglycidyl ether) 2.7Poly(allylamine/ethanediol diglycidyl ether) 2.3Poly(allyltrimethylammonium chloride 0.3 Poly(ethylenediamine)/acryloxychloride 1.2 Polyethyleneimine “C” 2.7 Polyethyleneimine “A” 2.2Poly(DET/EPI) 1.5 Polyethyleneimine “B” 1.2Poly(dimethylaminopropylacrylamide) 0.8 Poly(PEH/EPI) 0.7Poly(trimethylammoniomethyl styrene chloride) 0.7Poly(pentaethylenehaxaminemethacrylamide) 0.7Poly(tetraethylenepentaminemethacrylamide) 0.7Poly(diethylenetriaminemethacrylamide) 0.5Poly(triethylenetetramineethacrylamide) 0.5Poly(aminoethylmethacrylamide) 0.4 Poly(vinylamine) 0.4 Poly(MAPTAC)0.24 Poly(methylmethacrylate/PEI) 0.2 Poly(dimethylethyleneiminechloride) 0.2 Poly(diethylaminopropylmethacrylamide) 0.1Poly(guanidinoacrylamide) 0.1 Poly(guanidinobutylacrylamide) 0.1Poly(guanidinobutylmethacrylamide) 0.1

[0045] Table 2 shows results obtained using various other materials tobind phosphate. TABLE 2 Phosphate Bound Polymer (meq/g)* CalciumChloride 4.0 Calcium Lactate 2.4 Ox-Absorb ® 0.5 Maalox Plus ® 0.3Sephadex DEAE A-25, 40-125 m 0.2 Aluminum Hydroxide, Dried Gel 0.2

[0046] Table 3 shows results obtained for a variety of salts made frompolyethyleneimine and organic and inorganic acids. TABLE 3 PhosphateBound Polymer (meq/g)* Poly(ethyleneimine sulfate A) 0.9Poly(ethyleneimine sulfate B) 1.2 Poly(ethyleneimine sulfate C) 1.1Poly(ethyleneimine sulfate D) 1.7 Poly(ethyleneimine tartrate A) 0.7Poly(ethyleneimine tartrate B) 0.9 Poly(ethyleneimine tartrate C) 1.1Poly(ethyleneimine ascorbate A) 0.55 Poly(ethyleneimine ascorbate B)0.65 Poly(ethyleneimine ascorbate C) 0.9 Poly(ethyleneimine citrate A)0.7 Poly(ethyleneimine citrate B) 1.0 Poly(ethyleneimine citrate C) 0.9Poly(ethyleneimine succinate A) 1.1 Poly(ethyleneimine succinate B) 1.3Poly(ethyleneimine chloride) 1.1

[0047] Oxabsorb® is an organic polymer that encapsulates calcium suchthat the calcium is available to bind to such ions as phosphate, but maynot be released by the polymer and thus is not supposed to be absorbedby the patient.

[0048] The amount of phosphate bound by all of these materials, bothpolymers and inorganic gels, is expected to vary as the phosphateconcentration varies. The graph FIG. 1 below shows the relationshipbetween the solution phosphate concentration and the amount of phosphatebound to poly(dimethylaminopropylacrylamide). Other polymers of theclass are expected to show a similar relationship.

[0049] In an alternate type of test, the polymer was exposed to anacidic environment prior to exposure to phosphate as might happen in apatient's stomach. The solid (0.1 g) was suspended in 40 mL of 0.1 MNaCl. This mixture was stirred for 10 minutes, and the pH was adjustedto 3.0 with 1 M HCl, and the mixture was stirred for 30 minutes. Themixture was centrifuged, the supernatant decanted, and the solidresuspended in 40 mL of 0.1 m NaCl. This mixture was stirred for 10minutes, the pH was adjusted to 3.0 with 1 M HCl, and the mixture wasstirred for 30 minutes. The mixture was centrifuged, the supernatantdecanted, and the solid residue used in the usual phosphate assay.Results are shown in Table 4 for a variety of polymers and for aluminumhydroxide dried gel. In most cases the values for the amount ofphosphate bound are higher in this test than in the usual assay. TABLE 4Phosphate Bound Polymer (meq/g)* Poly(ethyleneimine sulfate B) 1.2Poly(ethyleneimine sulfate C) 1.3 Poly(ethyleneimine tartrate B) 1.3Poly(ethyleneimine tartrate C) 1.4 Poly(ethyleneimine ascorbate B) 1.0Poly(ethyleneimine ascorbate C) 1.0 Poly(ethyleneimine citrate B) 1.0Poly(ethyleneimine citrate C) 1.3 Poly(ethyleneimine succinate A) 1.1Poly(ethyleneimine succinate B) 1.3 Poly(ethyleneimine chloride) 1.4Aluminum Hydroxide 0.7

[0050] Rat Dietary Phosphorus Excretion Model

[0051] Six 6-8 week old Sprague-Dawley rats were placed in metaboliccages and fed semi-purified rodent chow powder containing 0.28%inorganic phosphorus. The diets were supplemented with 1.7%poly(allylamine/epichlorohydrin) or micro-crystalline cellulose; theanimals served as their own controls by receiving cellulose orpoly(allylamine/epichlorohydrin) in randomized order. The rats were fedad libitum for three days to acclimate to the diet. Feces excretedduring the next 48 hours were collected, lyophilized, and ground intopowder. The inorganic phosphate content was determined according to themethod of Taussky and Shorr: Microdetermination of Inorganic Phosphate.One gram of powdered feces was burned to remove carbon, then ashed in a600° C. oven. Concentrated HCl was then added to dissolve thephosphorus. The phosphorus was determined with ferrous sulfate-ammoniummolybdate reagent. Intensity of the blue color was determined at 700 nmon a Perkin-Elmer spectrophotometer through a 1 cm cell.

[0052] The results are shown in FIG. 2. Fecal phosphate concentrationincreased in all animals.

[0053] Urinary Phosphate Excretion in Partially Nephrectomized Rats

[0054] Sprague-Dawley rats, approximately 8 weeks old, were 75%nephrectomized. One kidney was surgically removed; approximately 50% ofthe renal artery flow to the contralateral kidney was ligated. Theanimals were fed a semi-purified rodent chow containing 0.385% inorganicphosphorus and either 10% poly(allylamine/epichlorohydrin) or cellulose.Urine was collected and analyzed for phosphate content on specific days.Absorbed dietary phosphate is excreted into the urine to maintain serumphosphate.

[0055] The results are shown in FIG. 3. None of the animals becamehyperphosphatemic or uremic, indicating that the residual kidneyfunction was adequate to filter the absorbed phosphate load. The animalsreceiving the poly(allylamine/epichlorohydrin) demonstrated a trendtowards reduced phosphate excretion, indicative of reduced phosphateabsorption.

[0056] Syntheses

[0057] Poly(allylamine hydrochloride)—To a 5 L, water jacketed reactionkettle equipped with 1) a condenser topped with a nitrogen gas inlet and2) a thermometer and 3) a mechanical stirrer was added concentratedhydrochloric acid (2590 mL). The acid was cooled to 5° C. usingcirculating water in the jacket of the reaction kettle at 0° C.Allylamine (2362 mL; 1798 g) was added dropwise with stirring,maintaining a temperature of 5-10° C. After the addition was complete,1338 mL of liquid was removed by vacuum distillation at 60-70° C.Azobis(amidinopropane) dihydrochloride (36 g) suspended in 81 mL waterwas added. The kettle was heated to 50° C. under a nitrogen atmospherewith stirring for 24 hours. Azobis(amidinopropane) dihydrochloride (36g) suspended in 81 mL water was again added and the heating and stirringcontinued for an additional 44 hours. Distilled water (720 mL) was addedand the solution allowed to cool with stirring. The liquid was addeddropwise to a stirring solution of methanol (30 L). The solid was thenremoved by filtration, resuspended in methanol (30 L), stirred 1 hour,and collected by filtration. This methanol rinse was repeated once moreand the solid was dried in a vacuum oven to yield 2691 g of a granularwhite solid (poly(allylamine hydrochloride).

[0058] Poly(Allylamine/Epichlorohydrin)—To a 5 gallon bucket was addedpoly(allylamine hydrochloride) (2.5 kg) and water 10 L). The mixture wasstirred to dissolve and the pH was adjusted to 10 with a solid NaOH. Thesolution was allowed to cool to room temperature in the bucket andepichlorohydrin (250 mL) was added all at once with stirring. Themixture was stirred gently until it gelled after about 15 minutes. Thegel was allowed to continue curing for 18 hours at room temperature. Thegel was then removed and put into a blender with isopropanol (about 7.5L). The gel was mixed in the blender with about 500 mL isopropanol for˜3 minutes to form coarse particles and the solid was then collected byfiltration. The solid was rinsed three times by suspending it in 9gallons of water, stirring the mixture for 1 hour, and collecting thesolid by filtration. The solid was rinsed once by suspending it inisopropanol (60 L), stirring the mixture for 1 hour, and collecting thesolid by filtration. The solid was dried in a vacuum oven for 18 hoursto yield 1.55 Kg of a granular, brittle, white solid.

[0059] Poly(Allylamine/Butanedioldiglycidyl Ether)—To a 5 gallon plasticbucket was added poly(allylamine hydrochloride) (500 g) and water (2 L).The mixture was stirred to dissolve and the pH was adjusted to 10 withsolid NaOH (142.3 g). The solution was allowed to cool to roomtemperature in the bucket and 1,4-butanedioldiglycidyl ether (130 mL)was added all at once with stirring. The mixture was stirred gentlyuntil it gelled after 4 minutes. The gel was allowed to continue curingfor 18 hours at room temperature. The gel was then removed and dried ina vacuum oven at 75° C. for 24 hours. The dry solid was ground andsieved for −30 mesh and then suspended in 6 gallons on water. Afterstirring for 1 hour the solid was filtered off and rinse processrepeated twice more. The solid was rinsed twice in isopropanol (3gallons), and dried in a vacuum oven at 50° C. for 24 hours to yield 580g of a white solid.

[0060] Poly(Allylamine/Ethanedioldiglycidyl Ether)—To a 100 mL beakerwas added poly(allylamine hydrochloride) (10 g) and water (40 mL). Themixture was stirred to dissolve and the pH was adjusted to 10 with solidNaOH. The solution was allowed to cool to room temperature in the beakerand 1,2 ethanedioldiglycidyl ether (2.0 mL) was added all at once withstirring. The mixture was allowed to continue curing for 18 hours atroom temperature. The gel was then removed and blended in 500 mL ofmethanol. The solid was filtered off and suspended in water (500 mL).After stirring for 1 hour the solid was filtered off and the risingprocess repeated. The solid was rinsed twice in isopropanol (400 mL),and dried in a vacuum oven at 50° C. for 24 hours to yield 8.7 g of awhite solid.

[0061] Poly(Allylamine/Dimethylsuccinate)—To a 500 mL round bottom flaskwas added poly(allylamine hydrochloride) (10 g), methanol (100 mL), andtriethylamine (10 mL). The mixture was stirred and dimethylsuccinate (1mL) was added. The solution was heated to reflux and stirring turned offafter 30 minutes. After 18 hours the solution was cooled to roomtemperature and solid was filtered off and suspended in water (1 L).After stirring for 1 hour the solid was filtered off and the rinseprocess repeated twice more. The solid was rinsed once in isopropanol(800 mL), and dried in a vacuum oven at 50° C. for 24 hours to yield 5.9g of a white solid.

[0062] Poly(Allyltrimethylammonium Chloride)—To a 500 mL three neckedflask equipped with a magnetic stirrer, a thermometer, and a condensertopped with a nitrogen inlet, was added poly(allylamine) crosslinkedwith epichlorohydrin (5.0 g), methanol (300 mL), methyl iodide (20 mL),and sodium carbonate (50 g). The mixture was then cooled and water wasadded to total volume of 2 L. Concentrated hydrochloric acid was addeduntil no further bubbling resulted and the remaining solid was filteredoff. The solid was rinsed twice in 10% aqueous NaCl (1 L) by stirringfor 1 hour followed by filtration to recover the solid. The solid wasthen rinsed three times by suspending it in water (2 L), stirring for 1hour, and filtering to recover the solid. Finally, the solid was rinsedas above in methanol and dried in a vacuum over at 50° C. for 18 hoursto yield 7.7 g of white granular solid.

[0063] Poly(Ethyleneimine)/Acryloyl Chloride—Into a 5 L three neck flaskequipped with a mechanical stirrer, a thermometer, and an additionalfunnel was added polyethyleneimine (510 g of a 50% aqueous solution(equivalent to 255 g of dry polymer) and isopropanol (2.5 L). Acryloylchloride (50 g) was added dropwise through the addition funnel over a 35minute period, keeping the temperature below 29° C. The solution wasthen heated to 60° C. with stirring for 18 hours. The solution wascooled and solid immediately filtered off. The solid was rinsed threetimes by suspending it in water (2 gallons), stirring for 1 hour, andfiltering to recover the solid. The solid was rinsed once by suspendingit in methanol (2 gallons), stirring for 30 minutes, and filtering torecover the solid. Finally, the solid was rinsed as above in isopropanoland dried in a vacuum over at 50° C. for 18 hours to yield 206 g oflight orange granular solid.

[0064]Poly(Dimethylaminopropylacrylamide)—Dimethylamino-propylacrylamide (10g) and methylene-bisacrylamide (1.1 g) were dissolved in 50 mL of waterin a 100 mL three neck flask. The solution was stirred under nitrogenfor 10 minutes. Potassium persulfate (0.3 g) and sodium metabisulfite(0.3 g) were each dissolved in 2-3 mL of water and then mixed. After afew seconds this solution was added to the monomer solution, still undernitrogen. A gel formed immediately and was allowed to sit overnight. Thegel was removed and blended with 500 mL of isopropanol. The solid wasfiltered off and rinsed three times with acetone. The solid white powderwas filtered off and dried in a vacuum oven to yield 6.1 g.

[0065] Poly(Methacrylamidopropyltrimethylammoniumchloride)=[Poly(MAPTAC)]-[3-(Methacryloylamino)propyl]trimethylammonium chloride (38 mLof 50% aqueous solution) and methylenebis-methacrylamide (2.2 g) werestirred in a beaker at room temperature. Methanol (10 mL was added andthe solution was warmed to 40° C. to fully dissolve the bisacrylamide.Potassium persulfate (0.4 g) was added and the solution stirred for 2minutes. Potassium metabisulfite (0.4 g) was added and stirring wascontinued. After 5 minutes the solution was put under a nitrogenatmosphere. After 20 minutes the solution contained significantprecipitate and the solution was allowed to sit overnight. The solid waswashed three times with isopropanol and collected by filtration. Thesolid was then suspended in water 500 (mL) and stirred for several hoursbefore being collected by centrifugation. The solid was again washedwith water and collected by filtration. The solid was then dried in avacuum oven to yield 21.96 g.

[0066] Poly(ethyleneimine) “A”—Polyethyleneimine (50 g of a 50% aqueoussolution; Scientific Polymer Products) was dissolved in water (100 mL).Epichlorohydrin (4.6 mL) was added dropwise. The solution was heated to55° C. for 4 hours, after which it had gelled. The gel was removed,blended with water (1 L) and the solid was filtered off. It wasresuspended in water (2 L) and stirred for 10 minutes. The solid wasfiltered off, the rinse repeated once with water and twice withisopropanol, and the resulting gel was dried in a vacuum oven to yield26.3 g of a rubbery solid.

[0067] Poly(ethyleneimine) “B” and Poly(ethyleneimine) “C” were made ina similar manner, except using 9.2 and 2.3 mL of epichlorohydrin,respectively.

[0068] Poly(methylmethacrylate-co-divinylbenzene)—Methylmeth-acrylate(50 g) and divinylbenzene (5 g) and azobisiso-butyronitrile (1.0 g) weredissolved in isopropanol (500 mL) and heated to reflux for 18 hoursunder a nitrogen 14 atmosphere. The solid white precipitate was filteredoff, rinsed once in acetone (collected by centrifugation), once in water(collected by filtration and dried in a vacuum oven to yield 19.4 g.

[0069]Poly(Diethylenetriaminemethacrylamide)—Poly(methyl-methacrylate-co-divinylbenzene)(20 g) was suspended in diethylenetriamine (200 mL) and heated to refluxunder a nitrogen atmosphere for 18 hours. The solid was collected byfiltration, resuspended in water (500 mL), stirred 30 minutes, filteredoff, resuspended in water (500 mL), stirred 30 minutes, filtered off,rinsed briefly in isopropanol, and dried in a vacuum oven to yield 18.0g.

[0070] Poly(Pentaethylenehexaminemethacrylamide)Poly(Tetraethylenepentamine-methacrylamide) andPoly(Triethylenetetraaminemethacrylamide) were made in a manner similarto poly(diethylenetriaminemethacrylamide) from pentaethylenehexamine,tetraethylenepentamine, and triethylenetetraamine, respectively.

[0071]Poly(methylmethacrylate/PEI)—Poly(methylmethacrylate-co-divinylbenzene)(1.0 g) was added to a mixture containing hexanol (9150 mL) andpolyethyleneimine (15 g in 15 g water). The mixture was heated to refluxunder nitrogen for 4 days. The reaction was cooled and the solid wasfiltered off, suspended in methanol (300 mL), stirred 1 hour, andfiltered off. The rinse was repeated once with isopropanol and the solidwas dried in a vacuum oven to yield 0.71 g.

[0072]Poly(aminoethylmethacrylamide)—Poly(methylmethacrylate-co-divinylbenzene)(20 g) was suspended in ethylenediamine 9200 mL) and heated to refluxunder a nitrogen atmosphere for 3 days. The solid was collected bycentrifugation, washed by resuspending it in water (500 mL), stirringfor 30 minutes, and filtering off the solid. The solid was washed twicemore in water, once in isopropanol, and dried in a vacuum oven to yield17.3 g.

[0073]Poly(diethylaminopropylmethacrylamide)—Poly(methyl-methacrylate-co-divinylbenzene)(20 g) was suspended in diethylaminopropylamine (200 mL) and heated toreflux under a nitrogen atmosphere for 18 hours. The solid was collectedby filtration, resuspended in water (500 mL), filtered off, resuspendedin water (500 mL), collected by filtration, rinsed briefly inisopropanol, and dried in a vacuum oven to yield 8.2 g.

[0074] NHS-acrylate—N-Hydroxysuccinimide (NHS, 157.5 g) was dissolved inchloroform (2300 mL) in a 5 L flask. The solution was cooled to 0° C.and acryloyl chloride (132 g) was added dropwise, keeping thetemperature 2° C. After addition was complete, the solution was stirredfor 1.5 hours, rinsed with water (1100 mL) in a separatory funnel anddried over anhydrous sodium sulfate. The solvent was removed undervacuum and a small amount of ethyl acetate was added to the residue.This mixture was poured into hexane (200 mL) with stirring. The solutionwas heated to reflux, adding more ethyl acetate (400 mL). The insolubleNHS was filtered off, hexane (1 L) was added, the solution was heated toreflux, ethyl acetate (400 mL) was added, and the solution allowed tocool to <10° C. The solid was then filtered off and dried in a vacuumoven to yield 125.9 g. A second crop of 80 g was subsequently collectedby further cooling.

[0075] Poly(NHS-acrylate)—NHS-acrylate (28.5 g), methylenebis-acrylamide(1.5 g) and tetrahydrofuran (500 mL) were mixed in a 1 L flask andheated to 50° C. under a nitrogen atmosphere. Azobisisobutyronitrile(0.2 g) was added, the solution was stirred for 1 hour, filtered toremove excess N-hydroxysuccinimide, and heated to 50° C. for 4.5 hoursunder a nitrogen atmosphere. The solution was then cooled and the solidwas filtered off, rinsed in tetrahydrofuran, and dried in a vacuum ovento yield 16.1 g.

[0076] Poly(guanidinobutylacrylamide)—Poly(NHS-acrylate) (1.5 g) wassuspended in water (25 mL) containing agmatine (1.5 g) which had beenadjusted to pH 9 with solid NaOH. The solution was stirred for 4 days,after which time the pH had dropped to 6.3. Water was added to a totalof 500 mL, the solution was stirred for 30 minutes and the solid wasfiltered off. The solid was rinsed twice in water, twice in isopropanol,and dried in a vacuum oven to yield 0.45 g.

[0077] Poly(Methacryloyl Chloride)—Methacryloyl chloride (20 mL),divinyl benzene (4 mL of 80% purity), AIBN (0.4 g), and THF (150 mL)were stirred at 60° C. under a nitrogen atmosphere for 18 hours. Thesolution was cooled and the solid was filtered off, rinsed in THF, thenacetone, and dried in a vacuum oven to yield 8.1 g.

[0078] Poly(Guanidinobutylmethacrylamide)—Poly(methacryloyl chloride)(0.5 g), agmatine sulfate (1.0 g), triethylamine (2.5 mL), and acetone(50 mL) were stirred together for 4 days. Water (100 mL) was added andthe mixture stirred for 6 hours. The solid was filtered off and washedby resuspending in water (500 mL), stirring for 30 minutes, andfiltering off the solid. The wash was repeated twice in water, once inmethanol, and the solid was dried in a vacuum oven to yield 0.41 g.

[0079] Poly(Guanidinoacrylamide)—The procedure forpoly-(guanidinobutylacrylamide) was followed substituting aminoguanidinebicarbonate (5.0 g) for the agmatine, yielding 0.75 g.

[0080] Poly(PEH/EPI)—Epichlorohydrin (1.5 g) was added dropwise to asolution containing pentaethylenehexamine (20 g) and water (100 mL),keeping the temperature between 65° C. The solution was stirred until itgelled and heating was continued for 4 hours (at 65° C.). After sittingovernight at room temperature the gel was removed and blended with water(1 L). The solid was filtered off, water was added (1 L), and theblending and filtration were repeated. The gel was suspended inisopropanol and the resulting solid was collected by filtration anddried in a vacuum oven to yield 28.2 g.

[0081] Ethylidenebisacetamide—Acetamide (118 g), acetaldehyde (44.06 g),copper acetate (0.2 g), and water (300 mL) were placed in a 1 L threeneck flask fitted with condenser, thermometer, and mechanical stirred.Concentrated HCl (34 mL) was added and the mixture was heated to 45-50°C. with stirring for 24 hours. The water was then removed in vacuo toleave a thick sludge which formed crystals on cooling to 5° C. Acetone(200 mL) was added and stirred for a few minutes after which the solidwas filtered off and discarded. The acetone was cooled to 0° C. andsolid was filtered off. This solid was rinsed in 500 mL acetone and airdried 18 hours to yield 31.5 g.

[0082] Vinylacetamide—Ethylidenebisacetamide (31.05), calcium carbonate(2 g) and celite 541 (2 g) were placed in a 500 mL three neck flaskfitted with a thermometer, a mechanical stirrer, and a distilling headatop a vigroux column. The mixture was vacuum distilled at 35 mm Hg byheating the pot to 180-225° C. Only a single fraction was collected(10.8 g) which contained a large portion of acetamide in addition to theproduct (determined by NMR). This solid product was dissolved inisopropanol (30 mL) to form the crude solution used for polymerization.

[0083] Poly(Vinylacetamide)—Crude vinylacetamide solution (15 mL),divinylbenzene (1 g, technical grade, 55% pure, mixed isomers), and AIBN(0.3 g) were mixed and heated to reflux under a nitrogen atmosphere for90 minutes, forming a solid precipitate. The solution was cooled,isopropanol (50 mL) was added, and the solid was collected bycentrifugation. The solid was rinsed twice in isopropanol, once inwater, and dried in a vacuum oven to yield 0.8 g.

[0084] Poly(Vinylamine)—Poly(vinylacetamide) (0.79 g) was placed in a100 mL one neck flask containing water 25 mL and concentrated HCl 25 mL.The mixture was refluxed for 5 days, the solid was filtered off, rinsedonce in water, twice in isopropanol, and dried in a vacuum oven to yield0.77 g. The product of this reaction (˜0.84 g) was suspended in NaOH (46g) and water (46 g) and heated to boiling (˜140° C.). Due to foaming thetemperature was reduced and maintained at ˜100° C. for 2 hours. Water(100 mL) was added and the solid collected by filtration. After rinsingonce in water the solid was suspended in water (500 mL) and adjusted topH 5 with acetic acid. The solid was again filtered off, rinsed withwater, then the isopropanol, and dried in a vacuum oven to yield 0.51 g.

[0085] Poly(trimethylammoniomethylstyrene chloride) is the copolymer oftrimethylammoniomethylstyrene chloride and divinyl benzene.

[0086] Poly(DET/EPI) is the polymer formed by reaction ofdiethylenetriamine and epichlorohydrin.

[0087] Poly(ethyleneimine) Salts—Polyethyleneimine (25 g dissolved in 25g water) was dissolved in water (100 mL) and mixed with toluene (1 L).Epichlorohydrin (2.3 mL) was added and the mixture heated to 60° C. withvigorous mechanical stirring for 18 hours. The mixture was cooled andthe solid filtered off, resuspended in methanol (2 L), stirred 1 hour,and collected by centrifugation. The solid was suspended in water (2 L),stirred 1 hour, filtered off, suspended in water (4 L), stirred 1 hour,and again filtered off. The solid was suspended in acetone (4 L) andstirred 15 minutes, the liquid was poured off, acetone (2 L) was added,the mixture was stirred 15 minutes, the acetone was again poured off,and the solid was dried in a vacuum oven to form intermediate “D”.

[0088] Poly(ethyleneimine sulfate A)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with sulfuric acid (1.1 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0089] Poly(ethyleneimine sulfate B)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with sulfuric acid (0.57 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0090] Poly(ethyleneimine sulfate C)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with sulfuric acid (0.28 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0091] Poly(ethyleneimine sulfate D)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with sulfuric acid (0.11 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0092] Poly(ethyleneimine tartrate A)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with tartaric acid (1.72 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0093] Poly(ethyleneimine tartrate B)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with tartaric acid (0.86 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0094] Poly(ethyleneimine tartrate C)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with tartaric acid (0.43 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0095] Poly(ethyleneimine Ascorbate A)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with ascorbic acid (4.05 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0096] Poly(ethyleneimine ascorbate B)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with ascorbic acid (2.02 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0097] Poly(ethylencimine Ascorbate C)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with ascorbic acid (1.01 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0098] Poly(ethyleneimine citrate A)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with citric acid (1.47 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0099] Poly(ethyleneimine citrate B)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with citric acid (0.74 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0100] Poly(ethyleneimine citrate C)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with citric acid (0.37 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0101] Poly(Ethyleneimine Succinate A)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with succinic acid (1.36 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0102] Poly(Ethyleneimine Succinate B)—Intermediate “D” (1.0 g) wassuspended in water (150 mL), stirred 30 minutes, and partiallyneutralized with succinic acid (0.68 g). The mixture was stirred anadditional 30 minutes, the solid was filtered off, resuspended inmethanol (200 mL), stirred 5 minutes, filtered off, and dried in avacuum oven.

[0103] Poly(Ethyleneimine Chloride)—Polyethyleneimine (100 g in 100 gwater) was dissolved in water (640 mL additional) and the pH wasadjusted to 10 with concentrated HCl. Isopropanol (1.6 L) was added,followed by epichlorohydrin (19.2 mL). The mixture was stirred undernitrogen for 18 hours at 60° C. The solids were filtered off and rinsedwith methanol (300 mL) on the funnel. The solid was rinsed byresuspending it in methanol (4 L), stirring 30 minutes, and filteringoff the solid. The rinse was repeated twice with methanol, followed byresuspension in water (1 gallon). The pH was adjusted to 1.0 withconcentrated HCl, the solid was filtered off, resuspended in water (1gallon), the pH again adjusted to 1.0 with concentrated HCl, the mixturestirred 30 minutes, and the solid filtered off. The methanol rinse wasagain repeated and the solid dried in a vacuum oven to yield 112.4 g.

[0104] Poly(Dimethylethylenimine Chloride)—Poly(ethyleneimine chloride)(5.0 g) was suspended in methanol (300 mL) and sodium carbonate (50 g)was added. Methyl iodide (20 mL) was added and the mixture heated toreflux for 3 days. Water was added to reach a total volume of 500 mL,the mixture stirred for 15 minutes, and the solid filtered off. Thesolid was suspended in water (500 mL), stirred 30 minutes, and filtered.The solid was suspended in water (1 L), the pH adjusted to 7.0 withconcentrated HCl, and the mixture stirred for 10 minutes. The solid wasfiltered off, resuspended in isopropanol (1 L), stirred 30 minutes,filtered off, and dried in a vacuum oven to yield 6.33 g.

[0105] Use

[0106] The methods of the invention involve treatment of patients withhyperphosphatemia. Elevated serum phosphate is commonly present inpatients with renal insufficiency, hypoparathyroidism,pseudohypoparathyroidism, acute untreated acromegaly, overmedicationwith phosphate salts, and acute tissue destruction as occurs duringrhabdomyolysis and treatment of malignancies.

[0107] The term “patient” used herein is taken to mean any mammalianpatient to which phosphate binders may be administered. Patientsspecifically intended for treatment with the methods of the inventioninclude humans, as well as nonhuman primates, sheep, horses, cattle,goats, pigs, dogs, cats, rabbits, guinea pigs, hamsters, gerbils, ratsand mice.

[0108] The compositions utilized in the methods of the inventions areorally administered in therapeutically effective amounts. Further, thepolymer are preferably non-toxic and stable upon administration. Atherapeutically effective amount of compound is that amount whichproduces a result or exerts an influence on the particular conditionbeing treated. As used herein, a therapeutically effective amount of aphosphate binder means an amount which is effective in decreasing theserum phosphate levels of the patient to which it is administered.

[0109] By “non-toxic” it is meant that when ingested in therapeuticallyeffective amounts neither the polymers nor any ions released into thebody upon ion exchange are harmful or are substantially harmful.

[0110] By “stable” it is meant that when ingested in therapeuticallyeffective amounts the polymers do not dissolve or otherwise decompose toform potentially harmful by-products, and remain substantially intact sothat they can transport bound phosphate out of the body.

[0111] The present pharmaceutical compositions are generally prepared byknown procedures using well known and readily available ingredients. Inmaking the compositions of the present invention, the polymericphosphate binder may be present alone, may be admixed with a carrier,diluted by a carrier, or enclosed within a carrier which may be in theform of a capsule, sachet, paper or other container. When the carrierserves as a diluent, it may be a solid, semi-solid or liquid materialwhich acts as a vehicle, excipient or medium for the polymer. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, syrups, aerosols, (as a solid orin a liquid medium), soft or hard gelatin capsules, sterile packagedpowders, and the like. Examples of suitable carrier, excipients, anddiluents include foods, drinks, lactose, dextrose, sucrose, sorbitol,mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates,propylhydroxybenzoates, and talc.

[0112] It should be understood, however, that the foregoing descriptionof the invention is intended merely to be illustrative by way of exampleonly and than other modifications, embodiments, and equivalents may beapparent to those skilled in the art without departing from its spirit.

What is claimed is:
 1. A method for removing phosphate from a patientcomprising orally administering to said patient a therapeuticallyeffective amount of a composition comprising at least one polymercharacterized by a repeat unit having the formula:

or a copolymer thereof, wherein each n is an integer, each R,independently, is H or a lower alkyl, alkylamino, or aryl group, andeach X⁻ is a carbonate or bicarbonate anion.
 2. The method of claim 1wherein said polymer is crosslinked with a crosslinking agent whereinsaid crosslinking agent is present in said composition from about 0.5%to about 75% by weight.
 3. The method of claim 2 wherein saidcrosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidylether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane,1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyldichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride,or pyromellitic dianhydride.
 4. The method of claim 2 wherein saidcrosslinking agent is present in said composition from about 2% to about20% by weight.
 5. The method of claim 1 wherein the polymer is acopolymer comprising a second repeat unit having the formula:

wherein each n, independently, is an integer and each R, independently,is H or a lower alkyl, alkylamino, or aryl group.
 6. The method of claim5 wherein said copolymer is crosslinked with a crosslinking agentwherein said crosslinking agent is present in said composition fromabout 0.5% to about 75% by weight.
 7. The method of claim 6 wherein saidcrosslinking agent comprises epichlorohydrin, 1,4 butanedioldiglycidylether, 1,2 ethanedioldiglycidyl ether, 1,3-dichloropropane,1,2-dichloroethane, 1,3-dibromopropane, 1,2-dibromoethane, succinyldichloride, dimethylsuccinate, toluene diisocyanate, acryloyl chloride,or pyromellitic dianhydride.
 8. The method of claim 6 wherein saidcrosslinking agent is present in said composition from about 2% to about20% by weight.
 9. A method for removing phosphate from a patientcomprising orally administering to said patient a therapeuticallyeffective amount of a composition comprising a copolymer characterizedby a repeat unit having the formula:

and a second repeat unit having the formula:

wherein said copolymer is crosslinked with epichlorohydrin, whereinepichlorohydrin is present in said composition from about 2% to about20% by weight and wherein each n is an integer, each R is H, and each X⁻0 is a carbonate or bicarbonate anion.
 10. A pharmaceutical compositioncomprising a carrier and a therapeutically effective amount of at leastone polymer characterized by a repeat unit having the formula:

or a copolymer thereof, wherein each n is an integer, each R,independently, is H or a lower alkyl, alkylamino, or aryl group, andeach X⁻ is a carbonate or bicarbonate anion.
 11. The pharmaceuticalcomposition of claim 11 wherein said polymer is crosslinked with acrosslinking agent wherein said crosslinking agent is present in saidcomposition from about 0.5% to about 75% by weight.
 12. Thepharmaceutical composition of claim 11 wherein said crosslinking agentcomprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane,1,3-dibromopropane, 1,2-dibromoethane, succinyl dichloride,dimethylsuccinate, toluene diisocyanate, acryloyl chloride, orpyromellitic dianhydride.
 13. The pharmaceutical composition of claim 11wherein said crosslinking agent is present in said composition fromabout 2% to about 20% by weight.
 14. The pharmaceutical composition ofclaim 10 wherein the polymer is a copolymer comprising a second repeatunit having the formula:

wherein each n, independently, is an integer and each R, independently,is H or a lower alkyl, alkylamino, or aryl group.
 15. The pharmaceuticalcomposition of claim 14 wherein said copolymer is crosslinked with acrosslinking agent wherein said crosslinking agent is present in saidcomposition from about 0.5% to about 75% by weight.
 16. Thepharmaceutical composition of claim 15 wherein said crosslinking agentcomprises epichlorohydrin, 1,4 butanedioldiglycidyl ether, 1,2ethanedioldiglycidyl ether, 1,3-dichloropropane, 1,2-dichloroethane,1,3dibromopropane, 1,2-dibromoethane, succinyl dichloride,dimethylsuccinate, toluene diisocyanate, acryloyl chloride, orpyromellitic dianhydride.
 17. The pharmaceutical composition of claim 15wherein said crosslinking agent is present in said composition fromabout 2% to about 20% by weight.
 18. A pharmaceutical compositioncomprising a carrier and a therapeutically effective amount of acopolymer characterized by a repeat unit having the formula:

and a second repeat unit having the formula:

wherein said copolymer is crosslinked with epichlorohydrin, whereinepichlorohydrin is present in said composition from about 2% to about20% by weight and wherein each n is an integer, each R is H, and each X⁻is a carbonate or bicarbonate anion.